Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Heart failure wikipedia , lookup
Coronary artery disease wikipedia , lookup
Cardiac contractility modulation wikipedia , lookup
Management of acute coronary syndrome wikipedia , lookup
Electrocardiography wikipedia , lookup
Hypertrophic cardiomyopathy wikipedia , lookup
Myocardial infarction wikipedia , lookup
Quantium Medical Cardiac Output wikipedia , lookup
Antihypertensive drug wikipedia , lookup
Heart arrhythmia wikipedia , lookup
Ventricular fibrillation wikipedia , lookup
Arrhythmogenic right ventricular dysplasia wikipedia , lookup
Pharmacology of Antiarrhythmics and Vasoactive Substances Department of pharmacology Liming zhou 2007,spring Cardiac Anatomy Cardiac Action Potential – Depolarisation due to opening of Na+ channels. 1 – Repolarisation due to inactivation of Na+ channels (fast Na+ channels, activation of K+ channels that let K+ out of the cell. 0 – Plateau phase. Due to slow inward current caused by Ca2+ channels (L-type Ca2+ channels) opening. This Ca2+ influx also leads to cardiac muscle contraction. 2 – Repolarisation due to K+ leaving cells. 3 – Spontaneous depolarisation to threshold where critical voltage activates Na+ channels. If this phase is steeper, then heart rate increases. Involves the spontaneous action of various channel types. 4 How is cardiac contraction triggered? Ca2+-induced Ca2+ release mechanism (+ve feedback) caused by Ca2+ binding to receptors on sarcoplasmic reticulum (SR) Actin and myosin filaments activated when [Ca2+]i rises This is the SLIDING FILAMENT THEORY The ryanodine receptor exists on the SR in many cell types and triggers Ca2+ release Ryanodine is a plant alkaloid that can bind to receptors Ryanodine receptors are composed of 4 identical sub-units, exists in T-tubules, and allows release of Ca2+ from the SR into the cytosol Cardiac muscle and tetanus muscle – only active when contraction required Cardiac muscle – only relaxes in between beats for short periods and must remain active Skeletal Cardiac ATP supply must be maintained: •Mitochondria are larger and greater in number •Cells contain myoglobin for more efficient use and storage of O2 Skeletal muscle can produce a maintained contraction (tetanus) Cardiac muscle unable to produce tetanus since prolonged refractory period prevents re-excitation Frank-Starling Mechanism As blood moves into the heart, it stretches the cardiac muscle In exercise, more blood enters the heart, stretching it even more Extra stretch produces extra force Expels larger volume of blood Enables us to handle increased blood volume Unique Thus, to cardiac muscle we have increased force on demand Frank-Starling Mechanism Most important function is to balance the outputs of left and right ventricles If output of right ventricle exceeds left: • • • • • Pulmonary volume increases Increased pressure in pulmonary veins Left ventricular (LV) filling pressure increases LV becomes more distended (stretched) Increased stroke volume Why can the myocardium increase force of contraction in response to increased filling pressure? 2 mechanisms: (1) Overlap of actin filaments causing mechanical interference at sarcomere lengths below 2 mM, so need to stretch more to contract muscle more sarcomere (2) As muscles stretched, sensitivity to calcium increases (this may involve troponin, the protein that regulates access to binding sites on actin) Mechanism of arrhythmic Antiarrhythmic drug Antiarrhythmic Classification Class I - Fast Channel Blockers • Ia - Quinidine, Disopyramide, Procainamide • Ib - Lidocaine, Phenytoin, Mexilitine, Tocaininde • Ic - Ecainide, Flecainide, Propafenone, Indecainide, Moricizine Antiarrhythmic Classification Class II - Beta Blockers • Propanolol, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Labetalol, Metoprolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol Antiarrhythmic Classification Class III • Bretylium, Amiodarone, Sotalol Class IV - Calcium Channel Blockers • Verapamil, Diltiazem Unclassified - Digoxin, Adenosine, Mg Procainamide - Actions Suppresses automaticity • decreasing the rate and amplitude of phase 4 diastolic depolarization • prolongs action potential duration • reduces the speed of impulse conduction • suppresses fibrillatory activity in the atria and ventricles Dose dependant anticholinergic activity Procainamide - Actions Negative Inotrope • more pronounced in ischemic myocardium Hypotension in high doses • vasodilatation of peripheral vasculature Procainamide- Pharmacokinetics Onset • 5 - 10 minutes IV • 15 - 60 minutes IM Half Life • 2.5 to 4.7 hrs in normal renal function • increased in CHF, Renal Failure Metabolized to N-acetyl Procainamide • NAPA Procainamide - Indications Ventricular arrhythmias • Stable Ventricular Tachycardia • Premature Ventricular Contractions • Ventricular Fibrillation / Pulseless VT Supraventricular tachyarrhythmias • PSVT, PAT, paroxysmal AV junctional • Atrial flutter and fibrillation Procainamide- Contraindications AV block • Second or third degree Long QT interval Torsade de pointes Caution • SLE, CHF, hepatic or renal disease Procainamide - Administration Continuous infusion safer than bolus Infusion of 20 - 30 mg/min until • control of arrhythmia • hypotension • QRS widens by > 50% • QT interval prolongation • Total of 17 mg/kg has been administered Procainamide - Administration Once ectopy is suppressed • maintenance drip of 1 to 4 mg/min Lower doses for CHF and renal failure Procainamide - Adverse Effects Myocardial Depression • prolonged QRS, QT, AV conduction, VF and Torsade de pointes Hypotension • High doses or rapidly administered Hypersensitivity • angioedema, bronchoconstriction, vascular collapse, febrile episodes, respiratory arrest Lidocaine - Actions Class IB antiarrhythmic • blocks fast sodium channels • decreases slope of phase 4 • decreased automaticity in the His-purkinje system • action potential duration and effective refractory period of His-purkinje increased • Acts preferentially on ischemic tissue Lidocaine - Actions Continued • Causes little or no effect on AV conduction • Elevates v-fib threshold • Supresses ventricular ectopy • negligible effect – autonomic nervous system – myocardial contractility – peripheral vascular tone Lidocaine -Pharmacokinetics Onset of Action • 30 to 60 seconds IV • 10 minutes IM Bolus administration necessary • infusion alone will not reach therapeutic levels for 30 min to several hrs. First pass metabolism • No PO form Lidocaine - Pharmacokinetics Half-Life (elimination) • 80 to 108 minutes – healthy patients • 7 hrs – in patients with CHF, liver disease Therapeutic Levels • 1.5 to 6 ug/ml • >5 ug/ml may cause CNS toxicity Lidocaine - Indications Drug of Choice • ventricular arrhythmias • ventricular ectopy frequent multifocal PVC’s (>6/min) – PVC couplets, salvos – long runs of VT – Not used for chronic PVC’s when asymptomatic Prophylactic use • No longer recommended Lidocaine - Administration Initial Dose IV • Ventricular Ectopy – 1 mg/kg bolus – additional doses of 0.5 mg/kg q 5-10 min • Ventricular Fibrillation – 1.5 mg/kg Total Dose IV • 3 mg/kg Lidocaine - Administration Endotracheal • If IV not available 1/2 • 2 to 2 times the dose diluted to total volume of 10 cc’s IM • 300 mg of 10% solution, deltoid vastus lateralis • Auto- injectors available Lidocaine - Adverse Effects CNS side effects Abrupt change in mental status Plasma levels greater than 9 ug/ml • psychosis, seizures, respiratory depression Contraindicated • SA or AV blocks • Known hypersensitivity Beta Blockers - Actions Block effects of catacholamines on Beta receptors Selective Beta blockers • metoprolol • acebutolol • atenolol • esmolol • metoprolol Beta Blockers - Actions Negative • Chronotropic – slows sinus rate – depresses AV conduction – Decreases cardiac output • Inotropic Vasodilatation Beta Blockers- Pharmacokinetics Onset • rapid - within 1 minute IV Half Life • 1 to 26 hours • Excretion is renal and GI Dose adjustment necessary for renal failure for some beta blockers Phillip L. Coule, M.D. Medical College of Georgia Emergency Medicine Beta Blockers - Administration Metoprolol • 5 mg IV push • selective B1 • Half life of 3-7 hrs Esmolol • ultra-short half life of 9 minutes • 25-50 ug/kg/min • load of 500 ug/kg not necessary Beta Blockers - Adverse Effects Similar for most Beta blockers • nausea, vomiting, light headedness, mental depression, bradycardia, hypotension, bronchospasm Contraindicated • > first degree heart block • CHF or cardiogenic shock • Caution with calcium channel blockers Bretylium - Actions Class III Biphasic Effects • Norepinephrine release – effects last 20 minutes • Blocks release of norepinephrine – 45 to 60 minutes after administration • Affects phase 3 (repolarization) prolongs refractoriness - antifibrillatory Bretylium - Indications VF • refractory VF, after epinephrine, lidocaine VT • refractory VT with a pulse, after lidocaine and procainamide Wide Complex Tachycardia Unknown • after lidocaine and adenosine Bretylium - Administration VF or Pulseless VT • 5 mg/kg rapid IV push • repeat at 10 mg/kg in 15 to 30 minutes • maximum is 35 mg/kg VT / ventricular arrhythmias • 5 - 10 mg.kg over 8 to 10 minutes Maintenance of 1-2 mg/min Diltiazem - Actions Class IV - Calcium Channel Blocker • decreases conduction velocity in diseased tissue • prolongs refractory period in AV node • slows discharge from SA node • minimal effect on normal tissue • Interrupts reentrant pathway in PSVT Diltiazem - Indications Rapid Conversion of PSVT • as effective as adenosine and verapamil Slowing of rate in A-Fib or A-flutter Hypertension Diltiazem - Administration PSVT, A-fib, A-flutter • .25 mg/kg (average 20 mg) over 2 minutes • Second bolus of .35 mg/kg Maintenance Infusion • 5-15 mg/hr Diltiazem - Adverse Effects Cardiovascular • angina, bradycardia, asystole, CHF, AV block, BBB, flushing, hypotension Non-cardiovascular • headache, dizziness, constipation, rash Adenosine - Actions Endogenous Nucleoside • produced by dephosphorylation of ATP Negative Chronotropic effects on SA and AV node • Does not alter accessory pathways • blockade of the AV node • potent vasodilator - no effects due to metabolism Adenosine - Pharmacokinetics Onset • 30 seconds Duration • 60 to 90 seconds Half-life • less than 7 seconds Adenosine - Indications Emergency management of PSVT • involving the AV node Diagnostic • Wide complex tachycardia of uncertain origin • detection of accessory pathways Adenosine - Administration 6 mg Rapid IV push (over 1-2 seconds) • most proximal port • followed by 20 ml saline flush • elevate the extremity after bolus Repeat Dosing • 12 mg rapid IV push if heart rate not decreased in 2 minutes Adenosine - Adverse Effects Minor and well tolerated • less than 1 minute • dyspnea, cough, syncope, vertigo, parasthesias Higher doses • Dipyramidole • Carbamazepine • Asthmatics, excessive coffee drinkers Magnesium - Actions Directly • Na, K+, ATPase pump Indirectly • calcium channel blocking activity Effects • Increases membrane potential • prolongs AV conduction • Corrects hypomagnesemia/hypokalemia Magnesium - Indications Intractable VF/VT Torsade de pointes May be useful • PVC’s, MAT, PSVT, digoxin toxicity Magnesium - Administration IV Loading dose • 1 to 2 grams in 50-100 cc of D5W over 1 to 2 minutes Acute MI • 8 to 12 grams per day in acute MI Vasoactive Medications Epinephrine Dopamine Norepinephrine Atropine Nitroglycerin Epinephrine - Overview Nonselective alpha and beta agonist • increased heart rate, SVR, ventricular contractility Onset • 1 to 2 minutes Duration of action • 2 to 10 minutes Epinephrine - Continued Indications • Cardiac Arrest • Bronchospasm • Anaphylaxis / hypersensitivity reactions Administration • Cardiac Arrest 1 mg IV push every 3 - 5 minutes – escalating and high dose options – Epinephrine - Continued • Endotracheal – 2 to 2.5 the IV dose diluted to 10 cc Adverse Effects • may increase myocardial oxygen consumption Dopamine - Overview Actions • acts on dopaminergic, alpha and beta receptors Low Dose • dilatation of renal, mesenteric, coronary, and intracerebral vascular beds • improves organ perfusion and increases urine output Dopamine - Continued Moderate Dose 2 - 10 ug/kg/min • mostly beta effects inotropic, chronotropic on heart – increased cardiac output – High Dose >10 ug/kg/min • Alpha effects predominate increased peripheral resistance – decreased blood flow to kidney – Norepinephrine - Overview Endogenous Catacholamine • powerful alpha agonist • potent vasoconstrictor Onset • 1 to 3 minutes Indications • severe hypotension refractory to fluids and other pressor agents Norepinephrine - Continued Specific Uses • Septic Shock • refractory hypotension due to AMI Dosing • 0.5 to 1 ug/kg/min increase by 1 to 2 ug/kg/min every 3-5 min – goal is systolic BP of 80 to 100 – Norepinephrine - Continued Adverse Effects • • • • • • ventricular irritability cardiac depression decreased renal blood flow reflex bradycardia acute hypertension – MAOI, TCA’s Extravasation necrosis – pentolamine 5-10 mg/10 cc subcutaneous Atropine Overview Antimuscarinic Agent • parasympatholytic / vagolytic – increases SA node automaticity by blocking vagus nerve Indications • hemodynamically unstable bradycardias • PEA, Asystole, bradyasystolic rhythms • anticholinergic properties Atropine Continued Dose • 0.5 to 1 mg IV Endotracheal • 1 to 2 mg IV (10 cc volume) Adverse effects • increased MVO2 • undesirable tachycardia • precipitate ventricular arrhythmias Summary Pharmacology of antiarrhythmic and vasoactive medications • Actions • Pharmacokinetics • Indications • Administration • Adverse Effects